Self-hardening calcium phosphate cements (CPC) have been used for bone and tooth restoration and for local drug delivery applications. See, for example, Larsson et al, “Use of injectable calcium phosphate cement for fracture fixation: A review,” Clinical Orthopedics and Related Research, 395:23-32 (2002) and Oda et al, “Clinical use of a newly developed calcium phosphate cement (XSB-671D),” Journal of Orthopedic Science, 11(2):167-174 (2006). The cements in powder form are typically mixed with an aqueous solution immediately before application. In the clinical situation, the ability of the surgeon to properly mix the cement powder and hydrating liquid and then place the cement paste in a defect within the prescribed time is a crucial factor in achieving optimum results. Specifically, the dry cement powder material needs to be mixed with an aqueous solution in the surgical setting, i.e., the operating room, transferred to an applicator, typically a syringe, and delivered to the desired location within the setting time. Conventional cements generally have a setting time of about 15-30 minutes. However, the methods used for mixing and transfer of cement for injection in the operating room are technically difficult and pose a risk for non-optimal material performance, e.g., early setting renders materials difficult to inject or causes phase separation, so called filter pressing. Further, for technical reasons and time constraints, the material is typically mixed with a hydrating liquid in bulk to form a paste and the paste is then transferred to smaller syringes for delivery. In practice, material is often wasted due to an early setting reaction, i.e., the hydrated material sets to a hardened cement prior to delivery to the desired location, or because too much material is being mixed. A solution to these problems that includes the possibility to deliver material in smaller quantities in a more controlled manner is thus desired.
There are two common setting chemistries for CPCs which result in two different end products after setting, hydroxyapatite (also referred to hydroxylapatite) and Brushite. The apatite product results from a neutral to alkaline reaction, whereas the Brushite product results from an acidic reaction. Apatite cements generally have longer resorption time than an acidic cement. See, for example, Constantz et al, “Histological, chemical, and crystallographic analysis of four calcium phosphate cements in different rabbit osseous sites,” Journal of Biomedical Materials Research, 43(4):451-461 (1998). However, the long resorption time for apatite cements can pose a problem in a clinical setting where the cement is used for bone restoration. That is, it is preferable to have a cement resorption rate similar to the formation rate of new bone so that the regeneration of the bone is not inhibited. This is not the case for many apatite cements. See, for example, Miyamoto et al, “Tissue response to fast-setting calcium phosphate cement in bone,” Journal of Biomedical Materials Research, 37(4):457-464 (1997). It has been shown that biphasic cements combining larger granules of, for example, β-tricalcium phosphate (β-TCP) in a matrix of brushite or apatite cement or alternative cements in combination with bioglass, result in better biological responses, i.e., faster bone in-growth, than cements without such additives. Another method to improve the biological response of cements, e.g., to provide faster bone in-growth, is via addition of silicon, strontium and/or fluoride to the cement composition. See, for example, Guo et al, “The influence of Sr doses on the in vitro biocompatibility and in vivo degradability of single-phase Sr-incorporated HAP cement,” Journal of Biomedical Materials Research Part A, 86A(4):947-958 (2008) and Camire et al, “Material characterization and in vivo behavior of silicon substituted alpha-tricalcium phosphate cement,” Journal of Biomedical Materials Research Part B—Applied Biomaterials, 76B(2):424-431 (2006). On the other hand, the acidic Brushite cements are difficult to use in a clinical setting due to their rapid setting reaction, involving the disadvantages discussed above.
Due to the fact that the cement precursor powders are anhydrous, it is difficult to handle powder with an average grain size below 1 micrometer. Such fine-grained materials have short shelf life and are also difficult to mix, especially in the operating room setting, due to very rapid setting times. The reactivity of the powders is related to the surface area, with a high surface area resulting in faster setting times and shorter shelf life. However, the strength of hardened cement materials obtained from fine-grained powders is higher than corresponding hardened cement materials formed from larger micrometer grain size materials, but the difficulties in handling and production discourage use of fine-grained powders.
In addition, injectable self-hardening biomaterials based on calcium silicates have been proposed for use in bone repair in orthopedics (see US 2006/0078590) and endodontics (see WO 94/24955). These self-hardening cements based on calcium silicates are similarly formed by mixing of powder and liquid to form a paste. However, the mixing procedure is often performed using a spatula or via a mechanical mixing system. Non-homogeneous mixing and the formation of air voids in the cement paste often result. Non-homogeneous mixed cement and/or air voids result in low mechanical strength and difficulties in delivering the cement through thin needles without obtaining phase separation between liquid and powder (the filter pressing effect). Moreover, these cements are fast setting and typically, in practice, the rheology of the cement can increase to such an extent that complete delivery by injection is impossible.
Self-hardening cements based on calcium aluminate cements have also been proposed to be used as biomaterial (see US 2008/0210125). The calcium aluminate cement materials have a beneficial mechanical strength profile compared to calcium phosphate cements, and in addition, the calcium aluminate materials are considered to be non-resorbable. However, due to the anhydrous nature of the calcium aluminate powders and their rapid hardening behavior, it is difficult to obtain a combined long shelf life and easy mixing to achieve optimal clinical results.
The problem of obtaining a proper mix of the powder material and hydrating liquid for optimum clinical results in apatite cements has been addressed in US 2006/0263443, US 2007/0092856, Carey et al, “Premixed rapid-setting calcium phosphate composites for bone repair,” Biomaterials, 26(24):5002-5014 (2005), Takagi et al, “Premixed calcium-phosphate cement pastes,” Journal of Biomedical Materials Research Part B—Applied Biomaterials, 67B(2):689-696 (2003), Xu et al, “Premixed macroporous calcium phosphate cement scaffold,” Journal of Materials Science—Materials in Medicine, 18(7):1345-1353 (2007), and Xu et al, “Premixed calcium phosphate cements: Synthesis, physical properties, and cell cytotoxicity,” Dental Materials, 23(4):433-441 (2007), wherein premixed pastes are described. In US 2006/0263443, for example, a powder composition for hydroxyapatite is premixed with an organic acid and glycerol to form a paste, which paste may subsequently be injected into a defect. The injected material hardens via the diffusion of body liquids into the biomaterial. The organic acid is added to increase resistance to washout and the end product after setting is apatite, which is known to have a long resorption time in vivo as described above. Also, compositions of β-tricalcium phosphate (β-TCP) and hydrated acid calcium phosphate in glycerin or polyethylene glycol have previously been described in CN 1919357. Han et al, “β-TCP/MCPM-based premixed calcium phosphate cements,” Acta Biomaterialia, doi:10.1016/j.actbio.2009.04.024 (2009), also discloses premixed cements.
However, there is a continuing need to be able to efficiently prepare and safely deliver hydraulic cements, particularly for biomedical applications, i.e., hydraulic cements that overcome the above noted and/or other difficulties of conventional hydraulic cement materials, while optionally optimizing performance properties.